Connection between Radiation-Regulating Functions of Natural Products and miRNAs Targeting Radiomodulation and Exosome Biogenesis

Exosomes are cell-derived membranous structures primarily involved in the delivery of the payload to the recipient cells, and they play central roles in carcinogenesis and metastasis. Radiotherapy is a common cancer treatment that occasionally generates exosomal miRNA-associated modulation to regulate the therapeutic anticancer function and side effects. Combining radiotherapy and natural products may modulate the radioprotective and radiosensitizing responses of non-cancer and cancer cells, but there is a knowledge gap regarding the connection of this combined treatment with exosomal miRNAs and their downstream targets for radiation and exosome biogenesis. This review focuses on radioprotective natural products in terms of their impacts on exosomal miRNAs to target radiation-modulating and exosome biogenesis (secretion and assembly) genes. Several natural products have individually demonstrated radioprotective and miRNA-modulating effects. However, the impact of natural-product-modulated miRNAs on radiation response and exosome biogenesis remains unclear. In this review, by searching through PubMed/Google Scholar, available reports on potential functions that show radioprotection for non-cancer tissues and radiosensitization for cancer among these natural-product-modulated miRNAs were assessed. Next, by accessing the miRNA database (miRDB), the predicted targets of the radiation- and exosome biogenesis-modulating genes from the Gene Ontology database (MGI) were retrieved bioinformatically based on these miRNAs. Moreover, the target-centric analysis showed that several natural products share the same miRNAs and targets to regulate radiation response and exosome biogenesis. As a result, the miRNA–radiomodulation (radioprotection and radiosensitization)–exosome biogenesis axis in regard to natural-product-mediated radiotherapeutic effects is well organized. This review focuses on natural products and their regulating effects on miRNAs to assess the potential impacts of radiomodulation and exosome biogenesis for both the radiosensitization of cancer cells and the radioprotection of non-cancer cells.


Introduction
Radiotherapy is a treatment for cancer in addition to chemotherapy and surgery. Radiation is an effective way to cure cancer development; however, it may incur damage to non-cancer tissues and cells, causing side effects. The efficiency of radiomodulators, such as radioprotectors and radiosensitizers, is constantly being improved to prevent tumor growth and migration and avoid side effects on non-cancer tissues [1]. Although radiation is a powerful therapy for the inhibition of cancer malignancies, improving the overall benefits of cancer therapy by protecting non-cancer cells from radiative effects with radioprotectors is desirable.
tumor growth and migration and avoid side effects on non-cancer tissues [1]. Although radiation is a powerful therapy for the inhibition of cancer malignancies, improving the overall benefits of cancer therapy by protecting non-cancer cells from radiative effects with radioprotectors is desirable.
In addition to proteins and lipids, exosomes are also rich in nucleic acids [49]. Among non-coding RNAs, the present review focuses on micro-RNAs (miRNAs) within exosomes, namely exosomal miRNAs, which are short oligonucleotides (~21-23 nt) that generally target the 3′ untranslated region (3′ UTR) of responsive genes that regulate their target gene expressions. Several reports have mentioned that natural products target specific miRNAs [50,51] that regulate diverse cellular responses. However, the potential role of natural-product-regulated miRNAs in the radiation-and exosome biogenesismodulating effects of natural products has not been investigated in detail ( Figure 1). Figure 1. The potential relationship between natural products, their associated miRNAs, radiomodulation, and exosome biogenesis. Natural products may regulate radiomodulation, exosome biogenesis, and miRNA responses. Moreover, there may be an interplay between radiomodulation and exosome biogenesis. However, there is a knowledge gap regarding the connection between miRNAs and radiomodulation/exosome biogenesis in natural product treatments. Radiomodulation attributes radioprotection to non-cancer tissues and has radiosensitizing effects on cancer tissues. This review focuses on radioprotective natural products and their potential miRNA changes to assess the potential impacts of radiomodulation and exosome biogenesis, because some radioprotective natural products may also possess radiosensitizing effects. Figure 1. The potential relationship between natural products, their associated miRNAs, radiomodulation, and exosome biogenesis. Natural products may regulate radiomodulation, exosome biogenesis, and miRNA responses. Moreover, there may be an interplay between radiomodulation and exosome biogenesis. However, there is a knowledge gap regarding the connection between miRNAs and radiomodulation/exosome biogenesis in natural product treatments. Radiomodulation attributes radioprotection to non-cancer tissues and has radiosensitizing effects on cancer tissues. This review focuses on radioprotective natural products and their potential miRNA changes to assess the potential impacts of radiomodulation and exosome biogenesis, because some radioprotective natural products may also possess radiosensitizing effects.
In addition to proteins and lipids, exosomes are also rich in nucleic acids [49]. Among non-coding RNAs, the present review focuses on micro-RNAs (miRNAs) within exosomes, namely exosomal miRNAs, which are short oligonucleotides (~21-23 nt) that generally target the 3 untranslated region (3 UTR) of responsive genes that regulate their target gene expressions. Several reports have mentioned that natural products target specific miRNAs [50,51] that regulate diverse cellular responses. However, the potential role of natural-product-regulated miRNAs in the radiation-and exosome biogenesis-modulating effects of natural products has not been investigated in detail ( Figure 1). Natural products may regulate several specific miRNAs to target many downstream signaling genes and thus modulate diverse cell functions by the natural-product-miRNA-downstream axis. This review focuses on downstream responses for radiation and exosome biogenesis in natural product treatments (Figure 1). Some literature reports have shown that several natural products are radiomodulators [2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17], and others offer miRNA modulation for radiation [7, and exosome biogenesis [93,. However, the natural-product-miRNA-downstream axis has two main knowledge gaps regarding the connections between natural products and miRNA regulation and between miRNA and the modulation of radiation and exosome biogenesis ( Figure 1).
The first gap relates to the fact that radiomodulation and miRNA changes have only been reported by separate studies. The relationship between radiomodulation and miRNAs in natural product treatments has not been investigated. The second gap concerns the fact that several miRNAs have radiation-modulating effects, but examining their downstream targets with a focus on radiation-and exosome biogenesis-modulating targets has been rare. Notably, many targets related to radiation and exosome biogenesis modulation have not been investigated in these natural product and miRNA studies.
In this review, we introduce bioinformatic tools (miRDB [167] and Gene Ontology in the Mouse Genome Database (MGD) [168]) to address these knowledge gaps. miRDB [167] can provide miRNA target prediction using a bioinformatics tool, MirTarget, based on thousands of miRNA-target interaction reports and machine learning for common miRNA binding features. MGD [168] is the authoritative database for biological reference information related to gene functions and phenotypes for several diseases. The Gene Ontology function in MGD [168] provides comprehensive gene signaling information for specific cell functions and responses, such as radiation and exosome biogenesis. miRDB [167] provides a straightforward search for targets by inputting miRNA names. The combination of Gene Ontology and miRDB allowed the natural-product-regulated miRNAs to easily retrieve their potential radiation and exosome biogenesis targets and fill these gaps. The bioinformatic application is described in detail later.
This review connects radioprotective natural products to miRNAs (Section 2). Their radiomodulating potential for non-cancer and cancer cells was assessed by a detailed literature search. Next, the potential roles of radiation-(Section 3) and exosome biogenesis-(Section 4) modulating effects in these miRNAs acting on non-cancer and cancer cells were explored by performing PubMed/Google Scholar, Gene Ontology [168], and miRDB [167] bioinformatic searches. Finally, the target genes and an overview of radiation-(Section 5) and exosome biogenesis-(Section 6) modulating effects are presented. In short, this review explores the connection between and miRNA basis of the radiation-and exosome biogenesis-modulating effects of radioprotective natural products, which may also have radiosensitizing effects on cancer cells. The interconnection of the radiation-induced regulation of exosomes and the cellular processes that govern extracellular vesicle biology is essential to shed light on the functionalities of these vesicles. There is an extraordinary wealth of information about the radiation-mediated release of non-coding-RNA-loaded exosomes from donor cells.
Recently, several natural product studies highlighted the importance of miRNAs in terms of their biological effects, but they did not focus on their radiation-modulating functions. Although radioprotective natural products (Table 1) have been mentioned in several literature reports, the participation of miRNAs in regulating the radiation response of cancer cells lacks a detailed investigation. The potential of the miRNA-modulating effects of these radioprotective natural products needs further assessment through a literature search and subsequent experimental investigations.
According to our PubMed/Google Scholar search, some miRNA changes have been reported in several radioprotective natural product treatments, but these studies did not investigate the radiation-modulating effects of these miRNAs (Table 1).
According to the literature search, some studies on natural products related to noncancer radiation are available (Section 2.1), while others have investigated natural products in relation to cancer radiation (Section 2.2). Some natural products have been included in both non-cancer and cancer radiation studies (Section 2.3). Notably, some natural products addressed in non-cancer radiation studies have been reported in cancer radiation studies and vice versa, but this review cannot consider all of them. They are listed in Table 1.

Function of Radioprotective Natural Products in Non-Cancer Tissue Studies
Several natural products regulate the expression of certain miRNAs in non-cancer tissues, but their radiomodulating effects have not been examined in the literature, as shown below. In non-cancer radiation studies, several radioprotective natural products (Table 1) [2,5,6,9,12], such as apigenin, berberine, celastrol, chlorogenic acid, daidzein, diosmin, melatonin, silymarin, thymol, troxerutin, vitamin C, and zingerone, have been shown to avoid side effects on non-cancer tissues. These radioprotective natural products and their miRNA changes have been reported individually. Moreover, the connection between radioprotective natural products and miRNA function has not been investigated in detail.
Consequently, several radioprotective miRNA candidates have been retrieved from radioprotective natural products (Table 1). Modulating these miRNA candidates revealed their radioprotective functions to avoid potential side effects on non-cancer tissues and cells.
In brief, several anticancer miRNA candidates have been retrieved from several radioprotective natural products (Table 1). Modulating these miRNA candidates revealed the antiproliferative functions of several cancer cells. These examples suggest that some radioprotective natural products protect non-cancer tissues and have antiproliferative potential against cancer cells in terms of miRNAs. This warrants a detailed investigation into the radiosensitizing function of these radioprotective natural-product-derived anticancer miRNAs.

Function of Radioprotective Natural Products in Non-Cancer Tissue and Anticancer Studies
Some radioprotective natural products (Table 1) [2,[4][5][6][7]13,17], such as chrysin, delphinidin, ferulic acid, ginsenoside Rg1, ligustrazine, lycopene, piperine, resveratrol, and vitamin D3, have been investigated in both non-cancer and cancer radiation studies. They may avoid side effects on non-cancer tissues and cause anticancer effects. These radioprotective natural products and their miRNA changes have been individually assessed. Moreover, the connection between these radioprotective natural products and miRNA functions has rarely been reported.
Consequently, some miRNA candidates modulated by several radioprotective natural products (Table 1) provide both radioprotection for non-cancer cells and antiproliferation for cancer cells. A detailed investigation into the radioprotective and radiosensitizing functions of these natural-product-modulated miRNAs is warranted.
Thus, a detailed assessment of the potential impact of these natural products on miRNA regulation is warranted.

Connection between Natural-Product-Regulated miRNAs and Radiation-Modulating Effects
Several studies have focused on natural products with radiation-modulating potential ( Table 1). These natural products also show miRNA-modulating effects. However, the impacts of these miRNAs on the radiation-modulating function have not been investigated. This warrants a detailed assessment of the relationship between these miRNAs and radiation-modulating functions.
After an in-depth literature search, it was evident that several of the miRNAs mentioned in Table 1 showing radiation-modulating functions need further clarification. However, the literature reports have rarely assessed the participation of radiation-modulating genes. Radiation-modulating signaling is reported in the Mouse Genome Database via the Gene Oncology function (GO:0071480 and GO:0071481) [168], i.e., cellular response to gamma radiation and cellular response to X-rays (https://www.informatics.jax.org/vocab/ gene_ontology/GO:0071480 and https://www.informatics.jax.org/vocab/gene_ontology/ GO:0071481 (accessed on 1 June 2023)).
To investigate the potential impact of the natural-product-regulated miRNAs (Table 1) on radiation-associated signaling (GO:0071480 and GO:0071481) [168], the miRDB [167] was applied to the target prediction of these radiation-associated miRNAs ( Figure 2).
Following this strategy (Figure 2), several miRNAs associated with natural products and their potential connections to radiation-modulating effects and genes were assessed. Although these natural products are radioprotectors (Table 1; step 1), their modulated miRNAs (Table 1; step 2) were retrieved from different studies unrelated to radiation. The literature search was performed to test the potential effects of modifying these miRNAs on radiation (step 3). Notably, these miRNA candidates could impact both non-cancer and cancer cells, exhibiting radioprotection and radiosensitivity, respectively. Finally, these radiation-associated miRNAs were fed into miRDB [167] to predict the GO radiationmodulating targets (step 4).

Figure 2.
Strategy for filling the knowledge gap related to the connection between natural products, their associated miRNAs, and radiation-modulating targets. Through a PubMed/Google Scholar search, literature surveys for (1) radioprotective natural products and (2) natural-product-regulated miRNAs were performed (Table 1). Notably, several natural products were individually reported to have radioprotective and miRNA-modulating effects; however, the impact of miRNAs on the radiation response during treatment with these natural products remains unclear. (3) The radiation impact (radioprotection for non-cancer tissues and/or radiosensitivity for cancer cells) of these miRNAs was assessed by a literature search. Finally, (4) these miRNAs were fed into miRDB [167] to retrieve the GO radiation-modulating genes summarized from the Gene Ontology function in MGD (GO:0071480 and GO:0071481) [168].  (2) natural-product-regulated miRNAs were performed (Table 1). Notably, several natural products were individually reported to have radioprotective and miRNA-modulating effects; however, the impact of miRNAs on the radiation response during treatment with these natural products remains unclear. (3) The radiation impact (radioprotection for non-cancer tissues and/or radiosensitivity for cancer cells) of these miRNAs was assessed by a literature search. Finally, (4) these miRNAs were fed into miRDB [167] to retrieve the GO radiation-modulating genes summarized from the Gene Ontology function in MGD (GO:0071480 and GO:0071481) [168].
After the literature search ( Figure 2), several miRNAs were identified from non-cancer radiation studies (Section 3.1), while others were associated with cancer radiation studies (Section 3.2). Several miRNAs were associated with both non-cancer and cancer radiation studies (Section 3.3). Notably, some miRNAs investigated in non-cancer radiation studies were also reported in cancer radiation studies and vice versa, but this review cannot list them all. They are summarized in Table 2.

Some Natural-Product-Regulated miRNAs Are Highly Expressed in Non-Cancer Radiation Studies
In general, each miRNA may have hundreds of predicted target genes according to miRDB. The potential radiation-modulating genes were retrieved from the target search results after inputting natural-product-modulating miRNAs. Consequently, the potential radiation-modulating gene targets for the natural-product-modulating miRNAs were individually identified. The bioinformatic target prediction of radiation-modulating genes for each natural-product-modulating miRNA was performed using miRDB [167]. Some natural-product-regulated miRNAs in non-cancer tissues are upregulated by radiation (Table 2) [52][53][54][55][56][57], and their potential radiation-modulating targets are described below. All the potential radiation-modulating targets according to miRDB are referred to as radiation targets.
Consequently, these reports suggest that these natural products may have radiationmodulating effects on non-cancer cells in relation to their radiation-modulating genes predicted based on miRNA.

Some Natural-Product-Regulated miRNAs Can Function as Radioprotectors in Non-Cancer Tissues
Some natural-product-regulated miRNAs in non-cancer tissues may function as radioprotectors (Table 2) [58,59]. For example, rosmarinic acid alleviated radiation-induced pulmonary fibrosis by suppressing inflammation and ROS levels via the upregulation of miR-19b-3p [58], and its radiation targets CCND2 and MAP3K20 were identified (Table 2). Exosomal miR-124-5p overexpression alleviated the radiation-induced cognitive dysfunction and microglial activation of the irradiated brain [59], and its radiation targets DDIAS, YAP1, and TLK2 were identified (Table 2).
Consequently, these reports suggest that these natural products may have radioprotective effects on non-cancer cells in relation to their radiation-modulating genes predicted based on miRNA.

Some Natural-Product-Regulated miRNAs Can Function as Radiosensitizers in Cancer Cells
Some natural-product-regulated miRNAs exhibit radiosensitizing effects on cancer cells (Table 2) . For example, radiation upregulated miR-182-5p expression in Tlymphocyte cultures from healthy donors [178] and head/neck cancer (HNSCC) cells [303].
Consequently, these reports suggest that these natural products may have radiosensitizing effects on cancer cells in relation to their radiation-modulating genes predicted based on miRNA.
Consequently, these reports suggest that these natural products may have radioresistant effects on cancer cells in relation to their radiation-modulating genes predicted based on miRNA.

Function of Natural-Product-Regulated miRNAs in Both Non-Cancer and Cancer Radiation Studies
Some natural-product-regulated miRNAs, such as miR-34a-5p and miR-107, have been included in both non-cancer and cancer radiation studies (Table 2) [7,95,103]. For ex-ample, miR-34a-5p was upregulated in mouse liver tissue after whole-body irradiation [95]. EGCG improved the apoptosis and radiosensitivity of liver cancer cells by upregulating miR-34a-5p [7], and its radiation targets TMEM109 and GATA3 were identified (Table 2). miR-107 overexpression improved the radiosensitivity of prostate cancer cells [103]. In peripheral mononuclear blood cells, miR-107 was upregulated by radiation [52], and its radiation target TSPYL5 was identified ( Table 2).
In the cases of miR-34a-5p and miR-107, both are upregulated in non-cancer tissues and provide radiosensitivity for cancer cells. This warrants identifying drugs that regulate these miRNAs, which may have functions for radioprotection and radiosensitivity.

Connection between Natural-Product-Regulated miRNAs and Exosome Biogenesis-Modulating Effects
The connection between the radiation-modulating effects of natural products (Table 1) and their associated miRNA effects has been explored (Table 2). However, the impacts of these natural-product-regulated miRNAs on exosome biogenesis-modulating functions have not been reported as of yet. A detailed assessment of the relationship between miRNAs and exosome biogenesis-modulating functions is warranted.
Following the strategy outlined in Figure 3, several miRNAs associated with radiationmodulating natural products and their potential connections to exosome biogenesismodulating effects and target genes were assessed. Although the natural products were radioprotectors (Table 1; step 1), their modulated miRNAs (Table 1; step 2) were retrieved from studies unrelated to exosome biogenesis. A literature search was performed to test the potential effects of modifying these miRNAs on exosome biogenesis (step 3). Notably, miRNA candidates could impact exosome biogenesis for both non-cancer and cancer cells. Finally, exosome biogenesis-associated miRNAs were fed into miRDB to predict GO exosome biogenesis-modulating targets (step 4).
have not been reported as of yet. A detailed assessment of the relationship between miRNAs and exosome biogenesis-modulating functions is warranted.
Following the strategy outlined in Figure 3, several miRNAs associated with radiation-modulating natural products and their potential connections to exosome biogenesis-modulating effects and target genes were assessed. Although the natural products were radioprotectors (Table 1; step 1), their modulated miRNAs (Table 1; step 2) were retrieved from studies unrelated to exosome biogenesis. A literature search was performed to test the potential effects of modifying these miRNAs on exosome biogenesis (step 3). Notably, miRNA candidates could impact exosome biogenesis for both noncancer and cancer cells. Finally, exosome biogenesis-associated miRNAs were fed into miRDB to predict GO exosome biogenesis-modulating targets (step 4).
After the literature search (Figure 3), we identified some miRNAs that were addressed in non-cancer radiation studies (Section 4.1), while others were associated with cancer radiation studies (Section 4.2). Notably, some miRNAs included in non-cancer exosome studies were also reported in cancer exosome studies and vice versa (Section 4.3). However, this review cannot list them all, though some are described below (Table 3).  (Table 1). Next, (3) the impact on exosome biogenesis of these miRNAs was assessed in both non-cancer and cancer exosomes by a literature search. Finally, (4) these miRNAs were fed into miRDB [167] to retrieve the exosome biogenesis-modulating genes summarized from the Gene Ontology function in MGD (GO:1990182) [168].  (Table 1). Next, (3) the impact on exosome biogenesis of these miRNAs was assessed in both non-cancer and cancer exosomes by a literature search. Finally, (4) these miRNAs were fed into miRDB [167] to retrieve the exosome biogenesis-modulating genes summarized from the Gene Ontology function in MGD (GO:1990182) [168].
After the literature search (Figure 3), we identified some miRNAs that were addressed in non-cancer radiation studies (Section 4.1), while others were associated with cancer radiation studies (Section 4.2). Notably, some miRNAs included in non-cancer exosome studies were also reported in cancer exosome studies and vice versa (Section 4.3). However, this review cannot list them all, though some are described below (Table 3).
Consequently, these reports suggest that these natural products may have exosome biogenesis-modulating effects on non-cancer exosomes in related to their exosome biogenesismodulating genes predicted based on miRNA.

Function of Natural-Product-Regulated miRNAs in Cancer Exosome Studies
Several natural-product-regulated miRNAs modulating cancer exosomes are described below (Table 3) [93,106,. miR-15a-5p was overexpressed in cancerous exosomes to inhibit liver cancer cell proliferation [115], and its exosome targets MYO5B and VPS4A were identified (Table 3). Hypoxic glioblastoma cells generated more exosomes and a higher miR-182-5p content in exosomes than those in a normoxic state, improving angiogenesis, which was reversed by miR-182-5p knockdown [116], and its exosome targets RAB7A, ATP9A, and SDC1 were identified (Table 3). Liver cancer tissues and cell lines showed a lower level of miR-27a-3p than non-cancer controls. Exosomal miR-27a-3p derived from mesenchymal stem cells inhibited the proliferation and metastasis of liver cancer cells [117], and its exosome target SMPD3 was identified (Table 3).
Exosomal miR-107 was highly expressed in gastric cancer cells [130], and its exosome targets VPS4A and SDCBP were identified (Table 3). Exosomal miR-125b-5p enhanced the migration and EMT of pancreatic cancer cells, with the degree of metastasis proportional to the miR-125b-5p level [131], and its exosome target VPS4B was identified (Table 3). Exosomal miR-590-5p was overexpressed in the serum of gastric cancer patients [132]. High exosomal miR-590-5p suppressed the proliferation and migration of gastric cancer cells, and its exosome targets RAB11A and MYO5B were identified ( Table 3).
Consequently, these reports suggest that these natural products may have exosome biogenesis-modulating effects on cancer exosomes in relation to their exosome biogenesismodulating genes predicted based on miRNA.
To evaluate the potential interaction between radiation and exosome biogenesis targets, a protein-protein interaction analysis using the STRING database was conducted (Figure 4). Most GO-provided targets showed interaction within the same function for radiation or exosome biogenesis modulation. The analysis showed the complex interactions between targets of the radiation-modulating function. Similar interactions were demonstrated for the exosome biogenesis function. In addition to self-interaction for radiation-and exosome biogenesis-modulating targets, some exosome biogenesis-modulating targets could interact with radiation-modulating targets. radiation and exosome biogenesis modulation by natural-product-regulated miRNAs remains unclear.
To evaluate the potential interaction between radiation and exosome biogenesis targets, a protein-protein interaction analysis using the STRING database was conducted ( Figure 4). Most GO-provided targets showed interaction within the same function for radiation or exosome biogenesis modulation. The analysis showed the complex interactions between targets of the radiation-modulating function. Similar interactions were demonstrated for the exosome biogenesis function. In addition to self-interaction for radiation-and exosome biogenesis-modulating targets, some exosome biogenesismodulating targets could interact with radiation-modulating targets.  Tables 2 and 3. The potential protein-protein interactions of these targets was analyzed using the STRING database [307]. Radiation-and exosome biogenesis-modulating targets are grouped into top and bottom parts of the figure, respectively. The connecting lines indicate potential proteinprotein interactions between the proteins at the ends of each line. Proteins with no recorded interactions are shown on the right side without connecting lines.
For example, the exosome biogenesis target PARK2 may interact with the radiationmodulating targets HSF1, BCL2L1, and TP53. The exosome biogenesis target COPS5 may interact with the radiation-modulating targets CDKNIA, TP53, and ATM. The exosome biogenesis target TSG101 may interact with the radiation-modulating targets CDKNIA, TP53, MDM2. The exosome biogenesis target VPS4B may interact with the radiationmodulating target YAP1. The exosome biogenesis target SDC1 may interact with the radiation-modulating targets TP53 and HRAS. The exosome biogenesis target RAB7B may  Tables 2 and 3. The potential protein-protein interactions of these targets was analyzed using the STRING database [307]. Radiation-and exosome biogenesis-modulating targets are grouped into top and bottom parts of the figure, respectively. The connecting lines indicate potential protein-protein interactions between the proteins at the ends of each line. Proteins with no recorded interactions are shown on the right side without connecting lines.
For example, the exosome biogenesis target PARK2 may interact with the radiationmodulating targets HSF1, BCL2L1, and TP53. The exosome biogenesis target COPS5 may interact with the radiation-modulating targets CDKNIA, TP53, and ATM. The exosome biogenesis target TSG101 may interact with the radiation-modulating targets CDKNIA, TP53, MDM2. The exosome biogenesis target VPS4B may interact with the radiationmodulating target YAP1. The exosome biogenesis target SDC1 may interact with the radiation-modulating targets TP53 and HRAS. The exosome biogenesis target RAB7B may interact with the radiation-modulating targets NUCKS1 and BCL2L1. The exosome biogenesis target CD34 may interact with the radiation-modulating targets BCL2L1, TP53, MDM2, GATA3, and HRAS. Therefore, there may be an interplay between radiationmodulating targets and exosome biogenesis targets.
Collectively, natural-product-regulated miRNAs may control the expression of radiationand exosome biogenesis-modulating targets at the transcriptional level, while radiationand exosome biogenesis-modulating targets may participate in subtle protein-protein interactions to regulate natural-product-mediated radiomodulation and exosome biogenesis. This warrants a detailed assessment of the interaction between radiation and exosome biogenesis with experimental validation for natural product treatments in the future.

Overview of Natural Products That Regulate miRNAs to Modulate Radiation Responses
The relationship between natural products, their modulated miRNAs, and their potential radiation-modulating targets identified from mining miRDB was described with a focus on natural products and miRNAs (Tables 1-3). To address the final gene targeting, this miRNA-radiation-target axis was plotted by converging to their target genes (Table 4).
Different natural-product-regulated miRNAs may target the same radiation-modulating genes ( Figure 3). For example, ATM is targeted by miR-18a-5p and miR-181a-5p. BCL2L1 is targeted by let-7a-5p, let-7c-5p, and miR-98-5p. A similar target-miRNA relationship is shown in Figure 3, but this is not described due to the large number of miRNAs involved.
Consequently, the axis of natural products, miRNAs, and radiation-modulating targets is presented in Table 4. * Natural products with modulating effects were derived from Table 1. ↓ indicates that miRNAs were downregulated by natural products, while miRNAs without ↓ were upregulated by natural products. Radiation-modulated genes were mined from miRDB based on these miRNAs (retrieval date: 1 June 2023).
This review summarizes and evaluates the axis of natural products, miRNAs, and exosome biogenesis targets in Table 5.

Conclusions
Radiotherapy is effective in cancer treatments but is limited by its adverse side effects, particularly for non-cancer tissue and cell injury. Several radioprotectors have been developed, but natural products exhibiting less toxicity than chemical compounds are preferable radioprotectors. Although several radioprotective natural products have been reported, the potential radiomodulating mechanisms remain unclear, particularly for radiation-and exosome biogenesis-modulating signaling and miRNA-associated responses.
Radiation and natural products can modulate miRNAs and exosome biogenesis. That being said, there are some knowledge gaps related to the connections between radiomodulating natural products and miRNAs and between these miRNAs and target radiation-and exosome biogenesis-modulating genes. Introducing the bioinformatic tools miRDB and the GO database allowed us to retrieve the potential targets of miRNAs associated with radiomodulating natural products.
In the present review, we proposed a strategy to identify radioprotective natural products, find the miRNA candidates of these natural products, and start surveying the potential targets of radiation-and exosome biogenesis-modulating genes based on these miRNAs. According to the literature survey, these miRNA candidates were found to be responsive to radiation in non-cancer and/or cancer tissues. Some miRNAs showed radioprotective effects on non-cancer tissues, and some showed radiosensitive or radioresistant effects on cancer tissues ( Figure 5). Moreover, most of these targets for modulating radiation response and exosome biogenesis have rarely been investigated, providing a future direction to advanced the study of radiomodulative natural products.
A concern regarding radioprotectors for non-cancer tissues and cells is the unplanned protection of tumor tissues and cells from being killed by radiotherapy, thus leading to radioresistance [5]. In Table 1, apigenin, baicalein, CAPE, chrysin, curcumin, daidzein, EGCG, gallic acid, genistein, quercetin, resveratrol, silymarin, vitamin C, and zingerone were not reported to exhibit radioprotective effects on tumor cells [5]. In addition to radioprotector function (Table 1), some natural products, such as curcumin, emodin, genistein, resveratrol, berberine, celastrol, ursolic acid, vitamin D, withaferin A [308], EGCG, CAPE, quercetin, and fucoidan [4], have also been reported to exhibit radiosensitizing effects on cancer cells. Accordingly, these natural products show dual functions by improving radiosensitization [4,308] in cancer cells and radioprotection (Table 1) in non-cancer cells. Except for those mentioned above, the potential radiosensitive effects of the remaining radioprotectors (Table 1) were outside the scope of this review, because the present review mainly focused on radioprotective natural products.
illustration. The potential interaction between radiation and exosome biogenesis in natural product treatments needs further assessment using inhibitors against radiation and exosome biogenesis targets. Collectively, thoughtful investigation is required to validate the detailed changes in miRNAs and the potential targets for regulating radiomodulation and exosome biogenesis within radiation studies using natural products for wet experiments in the future.
In conclusion, this review presented well-organized connections between natural products, miRNAs, radiomodulation, and exosome biogenesis ( Figure 5), providing directions for future investigations into natural-product-based radiotherapy through the modulation of radiation-and exosome-biogenesis. Figure 5. Schematic summary. Many radioprotective natural products were searched for in the literature. Using these natural product candidates, their miRNA changes were retrieved. In view of the miRNAs, the potential targets for modulating radiation and exosome biogenesis were predicted by the bioinformatic tool miRDB. Literature reports also demonstrate that these miRNAs can regulate responses to radiation and exosome biogenesis. Interestingly, radioprotective natural products may modulate several miRNAs, and, in turn, miRNAs exert radioprotection/radiosensitization and exosome biogenesis in terms of miRDB target prediction. Some natural products may have radioprotective and radiosensitizing effects. Detailed investigations into the radiomodulation of natural products are warranted. Moreover, most of the abovementioned miRNAs are bifunctional for radiation and exosome biogenesis modulation, suggesting that their interaction may modulate the radiomodulation effects of natural products.  Acknowledgments: The authors thank our colleague Hans-Uwe Dahms for editing the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest. Figure 5. Schematic summary. Many radioprotective natural products were searched for in the literature. Using these natural product candidates, their miRNA changes were retrieved. In view of the miRNAs, the potential targets for modulating radiation and exosome biogenesis were predicted by the bioinformatic tool miRDB. Literature reports also demonstrate that these miRNAs can regulate responses to radiation and exosome biogenesis. Interestingly, radioprotective natural products may modulate several miRNAs, and, in turn, miRNAs exert radioprotection/radiosensitization and exosome biogenesis in terms of miRDB target prediction. Some natural products may have radioprotective and radiosensitizing effects. Detailed investigations into the radiomodulation of natural products are warranted. Moreover, most of the abovementioned miRNAs are bifunctional for radiation and exosome biogenesis modulation, suggesting that their interaction may modulate the radiomodulation effects of natural products.
Moreover, this review considered highly active substances of plant origin from terrestrial biota in great detail as radioprotectors. Some bioactive substances isolated from marine biota, such as algae and invertebrates of the world's oceans, were also described. Almost all isolated producers of marine biota have very promising anti-cancer activity. Marine biota are quite easy to grow on marine farms; therefore, the future of pharmacy combatting cancer lies in these active ingredients. A detailed investigation of radioprotectors derived from marine natural products is warranted in the future.
Notably, the resources of the miRDB targets for radiation-and exosome biogenesismodulating effects were derived from different cell types, which may incur different targets for various miRNAs. Notably, these potential targets for miRNAs were the predicted results of the miRDB and still need experimental validation. This review cannot exclude the possibility that natural products may regulate other functional miRNAs to modulate radiation and exosome biogenesis besides those mentioned here. The proposed rationale for the natural-product-miRNA-downstream axis still warrants a detailed illustration. The potential interaction between radiation and exosome biogenesis in natural product treatments needs further assessment using inhibitors against radiation and exosome biogenesis targets. Collectively, thoughtful investigation is required to validate the detailed changes in miRNAs and the potential targets for regulating radiomodulation and exosome biogenesis within radiation studies using natural products for wet experiments in the future.
In conclusion, this review presented well-organized connections between natural products, miRNAs, radiomodulation, and exosome biogenesis ( Figure 5), providing directions for future investigations into natural-product-based radiotherapy through the modulation of radiation-and exosome-biogenesis.